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Fractalkine signaling in psychiatric disorder : observations in the postmortem brain Hill, Sarah Louise


Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are debilitating psychiatric illnesses. Though the pathophysiology underlying each disorder is not yet understood, previous studies have suggested that altered immune function may play a role, with microglia, the brain’s resident immune cells, implicated in this process. A recent genetic association study and meta-analysis of microarray data indicated that dysregulation of CX3CR1, a microglial G-protein coupled receptor, may be associated with SCZ. Signaling between CX3CR1 and its neuronal ligand, fractalkine (CX3CL1), is proposed to mediate neuron-microglia interactions, recruiting microglia to synaptic sites and modulating changes in microglial activation status. However, it remains to be determined whether fractalkine is dysregulated in SCZ, BD, or MDD, or if fractalkine signaling is associated with microglial morphology and activation status, or synaptic density in these disorders. To this end, we quantified mRNA and protein expression of fractalkine, CX3CR1, and the disintegrin-like metalloproteinase 10 (ADAM10), involved in ectodomain shedding of fractalkine, in postmortem brain tissue from individuals with SCZ, BD, MDD and matched controls. We detected a significant decrease in fractalkine protein levels in SCZ relative to controls, suggesting fractalkine-CX3CR1 signaling may be disrupted in this disorder. Correlations were observed between fractalkine, CX3CR1, microglial measures and pre-synaptic protein levels.

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